Pivotal in the action of all drugs of abuse is the ability to alter, in some way, levels of consciousness, and to alter or distort sensory input or the subjective appreciation of sensory input. We propose to determine the effect of a series of abuse agents (THC, LSD, mescaline and morphine) on the CNS responses elicited by simultaneous or temporally coupled activation of multiple sensory modalities. We will test the hypothesis that the distortion of sensory input at some level in the input pathway, and more particularly at the polysensory cortex, may be correlated to the ability of an agent to induce phenomena such as hallucinations and synesthesia. By activation of multiple sensory modalities we hope to demonstrate actions of these agents that are not apparent when a single modality is driven in isolation. This technique will also allow us to determine whether facilitation or occlusion occurs in convergent pathways to polysensory cortical neurons and to further determine whether such neurophysiological mechanisms are sensitive to the test agents. The possibility that these pathways are subserved by cholinergic mechanisms will also be explored. We will also determine whether cholinergic mechanisms play a role in the modulation of sensory input by the reticular or limbic system. We will study the effects of the test agents at a second level of neuronal integration, namely the mechanisms involved in classical conditioning. We will utilize as a model the conditioned flexor response in the isolated spinal cord in situ. Drug effects on the conditioned and non-conditioned mechanical responses will be correlated to the electrical activity of the appropriate motoneuron pool. The information gained through these studies will contribute to our understanding of the complex interactions that occur when multiple modality specific pathways are activated. If, as is suspected, the various abuse agents have differential actions on sensory input projections to convergent pathways to polysensory cortex as well as to the neuronal substrate involved in conditioned responses, it is possible that the experimental models described here could be used to predict hallucinogenic properties of agents yet to be synthesized.